This proposal describes a 5-year training program for the development of a career as a physician- scientist. The principal investigator has completed a PhD thesis at the University at Buffalo in tumor immunology, and Pediatric residency and Allergy/Immunology fellowship training at the University of California at San Diego. She will expand upon her scientific skills through a focused career development plan and training in molecular genetics as applied to immune dysregulation in pediatrics. Dr. Hal Hoffman is a Professor of Pediatrics and Medicine at UC San Diego and will mentor the principal investigator's scientific and career development. Dr. Hoffman is a globally recognized leader in autoinflammatory disorders. An advisory committee of scientists, including Dr. Kelly Frazer who has expertise in the role of genomics in pediatric disease, will provide additional career and project guidance. In addition, intensive workshops, seminars, journal clubs, and specific laboratory technique training will accompany ample protected research time. The academic environment in the Department of Pediatrics at UCSD supports the development of independent, translational investigators. Scientific investigations will focus on the genetic and immunoregulatory mechanisms of Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome, a systemic inflammatory disorder of childhood characterized by recurrent episodes of fever, oropharyngeal signs, cervical adenitis and leukocytosis in otherwise healthy children. The underlying etiology of PFAPA is unknown and therapies are limited; both are issues which negatively impact the quality of life for patients and their families. The specific goals of this project are: 1) to identify the genetic basis of PFAPA syndrome using DNA collected from families with multiple members that have a history of PFAPA, 2) to investigate the patterns of gene expression in tissue from PFAPA patients undergoing tonsillectomy with a focus on IL-1-related pathways and B cells, and 3) to evaluate the role of DNA methylation and histone acetylation events in tonsils as a regulatory mechanism in the pathogenesis of PFAPA.